Tandem reactions formation-reduction

Formation of Chiral Quaternary Carbon. Birch reduction-alkylation of benzoic acids and esters establishes quaternary carbon centers. Neighboring stereocenters will influence the stereochemical outcome of the tandem reaction sequence. The following example illustrates how a chiral auxiliary (derived from prolinol) controls the stereoselection in the Birch reduction-alkylation step. ... 

S,3S,7S)-3,7-dimelhylpentadecan-2-yi propionate Pine sawflics Diprion species) Fs Tandem ester reduction-epoxide formation-reductive epoxide-opening reaction [196]... 

Sato determined that the use of Lewis acid was advantageous for tandem radical addition/reduction reactions in terms of both yield and selectivity [25]. As shown in Scheme 8, Lewis acid promoted the addition of the butyl radical to the a,fi-unsaturated ester, which in turn led to the formation of chelated transition state N. The improved selectivity was likely the result of a tighter complexation between the hydroxyl and carbonyl functions of the substrate and the aluminum atom. Nagano and collaborators used the same strategy with y-methoxy-a-methylenecarboxylic esters [26]. The use of La(fod)3 delivered a very good ratio of anti isomer in that reaction involving 1,3-asymmetric induction and a 7-membered cyclic transition state, illustrated by O in Scheme 8. 

S.3S.7Sl-3.7-dimethylpenladecan-2-yl propionate Pine sawflies Diprion species) Fs Tandem ester reduction-cpox ide formation-reductive epox ide-opening reaction (1961... 

Intermolecular and intramolecular HAMs are known. The transformation can be considered as a tandem reaction [2,3] consisting of three consecutive steps (i) hydroformylation, (ii) formation of an imine or an enamine, and (iii) reduction. Finally, the Af-alkylated amine is produced [4]. Clearly, these reactions can also be carried out in separate steps, but the application of uniform reaction conditions offers considerable advantages, such as the use of a single catalyst for the hydroformylation and the hydrogenation steps. Moreover, the equihbrium of the formation of the intermediate imine or enamine can be advantageously shifted by the irreversible hydrogenation in the last step [5]. 

Various transition metals have been used in redox processes. For example, tandem sequences of cyclization have been initiated from malonate enolates by electron-transfer-induced oxidation with ferricenium ion Cp2pe+ (51) followed by cyclization and either radical or cationic termination (Scheme 41). ° Titanium, in the form of Cp2TiPh, has been used to initiate reductive radical cyclizations to give y- and 5-cyano esters in a 5- or 6-exo manner, respectively (Scheme 42). The Ti(III) reagent coordinates both to the C=0 and CN groups and cyclization proceeds irreversibly without formation of iminyl radical intermediates.The oxidation of benzylic and allylic alcohols in a two-phase system in the presence of r-butyl hydroperoxide, a copper catalyst, and a phase-transfer catalyst has been examined. The reactions were shown to proceed via a heterolytic mechanism however, the oxidations of related active methylene compounds (without the alcohol functionality) were determined to be free-radical processes. 

The formation of l,2,5-trithiepan-4,6-dicarboxylates was explained by the mechanism depicted in Scheme 85 <20040BC2870>. This reaction presumably involves an initial reduction of 401 to A2-[l,2,3]thiazoline 405, which forms the S,C-biradical 406 by ring opening and release of nitrogen. Dimerization of 406 gives the S,C-biradical 407, which forms a C,C-biradical 409. A tandem intramolecular cyclization-expulsion of acrylic ester from 409 affords the trithiepine- dicarboxylates 402 and 403. An alternative pathway for the reaction would involve the formation of 408 from 406, which would be converted to 409 and then to the products. 

The mechanism of the catalytic cycle is outlined in Scheme 1.37 [11]. It involves the formation of a reactive 16-electron tricarbonyliron species by coordination of allyl alcohol to pentacarbonyliron and sequential loss of two carbon monoxide ligands. Oxidative addition to a Jt-allyl hydride complex with iron in the oxidation state +2, followed by reductive elimination, affords an alkene-tricarbonyliron complex. As a result of the [1, 3]-hydride shift the allyl alcohol has been converted to an enol, which is released and the catalytically active tricarbonyliron species is regenerated. This example demonstrates that oxidation and reduction steps can be merged to a one-pot procedure by transferring them into oxidative addition and reductive elimination using the transition metal as a reversible switch. Recently, this reaction has been integrated into a tandem isomerization-aldolization reaction which was applied to the synthesis of indanones and indenones [81] and for the transformation of vinylic furanoses into cydopentenones [82]. 

The desymmetrization of dicarbonate 206 was initiated by the addition of one equivalent of N-(3-butenyl) nosylamide 207 under palladium catalysis in the presence of Trost s chiral diphosphine ligand 205. When the first allylic substitution was completed, the reaction was warmed and the resulting intermediate 208 was treated in situ with one equivalent of a second nosylamide 209. Product 210 resulting from this double substitution reaction was submitted to a tandem intramolecular ROM/RCM to furnish key precursor 211, which was engaged in the final cyc-lization step by the reduction of the double bonds, followed by the HCl-promoted domino deprotection of the acetal and aminal formation. 

The tandem Mukaiyama aidoi reaction-Prins cyciization was utilized during the formal total synthesis of leucascandrolide A by S.D Rychnovsky. The addition of the activated aldehyde to the enol ether resulted in the formation of an oxocarbenium ion, which was captured intramolecularly by the allylsilane moiety to form a new tetrahydropyran ring. The reduction of the crude reaction mixture with NaBH4 was performed to remove the unreacted aldehyde starting material, thereby facilitating the chromatographic purification of the product. The product was isolated as a 5.5 1 mixture of epimers at C9. 

The samarium enolate radicals were also trapped intermolecularly, with formation of new carbon-carbon bonds, by quenching the reactions with suitable electrophiles The occurrence of these tandem rearrangements was possible because the samarium(II) iodide acted as a clean one-electron reductant and also generated the metal enolates. 

Arai et al. reported that asymmetric tandem cyclization of the dialkenyl alcohol 182 in the presence of Pd(II)— spiro bis(isoxazoline) catalyst gave the bicyclic heterocycle 183 in 89% yield with 82% ee (Scheme 61).132d The reaction proceeds through Wack-er-type oxypalladation, formation of the palladacycle 185 by carbopalladation of the resulting alkylpalla-dium intermediate 184, elimination of HX, and subsequent reductive elimination of Pd(0) to give the product 183. 

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